With the complete sequence of the mouse genome available, we can now study genetic variation from natural populations in different genomic regions, investigate the forces underlying that variation, and begin to identify functional variants. Significant efforts have gone into the description of single nucleotide polymorphisms (SNPs) among inbred laboratory strains of mice, yet little is known of how this variation relates to population-level variation in the wild. For example, many lab mouse SNPs may represent fixed interspecific differences between Mus domesticus and Mus musculus, while others may represent intraspecific polymorphisms segregating in one or both species. The proposed research will (1) document patterns of nucleotide variation in natural populations of M. domesticus and M. musculus by sequencing 5-10 kb at each of 15 genes on the X chromosome and 15 genes on autosomes and also sequencing these same genes in two closely related species of mice, M. spretus and M. caroli, (2) relate genetic variation in these natural populations to genetic variation among inbred strains by sequencing the same 30 genes in nine commonly used inbred strains and also by genotyping the wild mice for a set of 300 SNPs previously ascertained in inbred strains, (3) document patterns of intraspecific nucleotide polymorphism and interspecific divergence for a set of 12 genes known to be involved in reproduction and chosen as likely targets for selection, (4) provide a large-scale scan for the effects of natural selection by assaying microsatellite variation at 100 markers spaced along the X chromosome and 100 markers on chromosome 1, and (5) sequence a series of windows spaced at regular intervals adjacent to several loci identified as targets of selection from the work described above. The thirty genes on the X chromosome and autosomes will be compared to published polymorphism surveys of these same genes in humans. Because many of these genes are found in different genomic environments in mice and humans, this comparison will provide a direct test of the hypothesis that genomic context is an important determinant of patterns of genetic variation. The proposed research will provide the first comprehensive description of nucleotide variation in natural populations of M. domesticus and M. musculus and will provide a clear picture of the relationship between variation among commonly used inbred strains and variation in natural populations.